The aim of this project is to identify, characterize, and clone those genes that drive the development of neoplasia and whose malignant potential results from changes caused by chemical carcinogens. DNAase I-hypersensitive (HS) sites were identified as targets for rapid binding and repair following in vivo exposure to benzo(a)pyrene (BP), both in total liver cell DNA and in the c- Ha-ras-1 proto-oncogene. The kinetics of BP adduct formation and repair were first determined in total liver DNA from hamsters given tritiated BP intraportally. Isolation of nuclei after selected BP treatment times showed that 80% of the adducts were DNAase I-HS at early times after BP exposure (30 min), whereas the adducts remaining when repair was nearly complete (60 min) were no longer DNAase I-HS. The Ha-ras gene was analyzed under the same conditions of BP exposure in hamster liver DNA-and showed a marked DNAase I-HS response at the early time points (15-30 min), but not after repair completion (120 min), indicating that BP binding and repair occur preferentially at DNAase I-HS sites. DNAase I-HS sites were also found in the Ha-ras locus in human liver DNA, and human hepatoma DNA.